Nagamura S, Kanda Y, Kobayashi E, Gomi K, Saito H
Kyowa Hakko Kogyo Co., Ltd., Tokyo Research Laboratories, Japan.
Chem Pharm Bull (Tokyo). 1995 Sep;43(9):1530-5. doi: 10.1248/cpb.43.1530.
A series of duocarmycin B2 derivatives, modified at the phenolic hydroxyl group to ester, carbonate and carbamate, was synthesized. Antitumor activity of these analogs was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The stability of the compounds under aqueous conditions was examined, and we found a correlation between antitumor activity in vivo and stability in aqueous solution, that is, the more stable derivatives exhibited higher antitumor activity. Among these derivatives, the N,N-dialkylcarbamoyl analogs exhibited both improved antitumor activity and higher stability compared with duocarmycin B2. These analogs were subjected to further biological evaluation and they expressed broad-spectrum activity toward murine solid tumors M5076, Colon 26 and Colon 38, and human xenografted carcinoma MX-1.
合成了一系列在酚羟基处修饰为酯、碳酸酯和氨基甲酸酯的双卡霉素B2衍生物。通过HeLa S3细胞生长抑制试验（体外）和对小鼠肉瘤180的抗肿瘤活性试验（体内）对这些类似物的抗肿瘤活性进行了初步评估。研究了这些化合物在水性条件下的稳定性，我们发现体内抗肿瘤活性与水溶液稳定性之间存在相关性，即更稳定的衍生物表现出更高的抗肿瘤活性。在这些衍生物中，与双卡霉素B2相比，N，N-二烷基氨基甲酰基类似物既表现出提高的抗肿瘤活性又具有更高的稳定性。对这些类似物进行了进一步的生物学评估，它们对小鼠实体瘤M5076、结肠癌26和结肠癌38以及人异种移植癌MX-1表现出广谱活性。
